(1) Field of the Invention
The present invention relates to a process for preparing N-(substituted)-C-(substituted methyl)-oxazolidinones, C-(substituted methyl)-oxazolidinones, and N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably chiral, from optically active C-(protected oxymethyl)-oxazolidinones. The process can be used to produce combinatorial libraries of the above substituted oxazolidinones in a two or three step reaction comprising a plurality of reagents differing in numbers of carbons or particular substituted oxazolidinones. A number of substituted oxazolidinones produced using the above process have been discovered to have antimicrobial activity.
(2) Description of Related Art
Oxazolidinones, particularly substituted oxazolidinones such as 3-(substituted)-5-alkylaminomethyl- and 3-(substituted)-5-acylaminomethyl-2-oxazolidinones, are an important class of drug substances which are used for a wide variety of drug applications. These applications include use as antibacterial agents and in therapies for treating behavior disorders (Bowersock et al., Antimicrob. Agents Chemotherp. 44: 1367-1369 (2000); Skold, Acta Vet. Scand. Suppl. 93: 23-36 (2000); Diekema and Jones, Drugs 59: 7-16 (2000); Genin et al., J. Med. Chem. 43: 953-970 (2000); Johnson et al., J. Antimicrob. Chemother. 45: 225-230 (2000); Schulin et al., Antimicrob. Agents Chemotherp. 43: 2873-2876 (1999); Cynamon et al., Antimicrob. Agents Chemotherp. 43: 1189-1191 (1999); Chen and Reamer, Organic Letts. 1: 293-294 (1999); Brenner et al., Clin Therapeut. 22: 411-419 (2000); Clemett and Markham, Drugs 59: 815-827 (2000); Brickner et al., J. Med. Chem. 39: 673-679 (1996); Barry, Antimicrob. Agents Chemotherp. 32: 150-152 (1988); Slee et al., Antimicrob. Agents Chemotherp. 31: 1791-1797 (1987); Manninen et al., Abs. Paps. Amer. Chem. Soc. 212: 389-ORGN, Part 2, (Aug. 25, 1996)).
There are several methods for making the oxazolidinone nucleus in 3-(substituted)-5-alkylaminomethyl- and 3-(substituted)-5-acylaminomethyl-2-oxazolidinones. The general structure of 3-(substituted)-5-(substituted methyl)-2-oxazolidinone is
wherein R1 is alkyl, aryl, heteroalkyl, heteroaryl, or mixture thereof, or hydrogen or hydroxy, and R2 is alkyl, aryl, heteroalkyl, heteroaryl, or mixture thereof. The following disclose processes for preparing oxazolidinones and substituted oxazolidinones.
U.S. Pat. No. 6,288,238 B1 to Hollingsworth and Wang disclose a process for preparing 5-hydroxymethyl-2-oxazolidinones in one step from 3,4-boronic acid ester protected 3,4-dihydroxybutyramides.
U.S. Pat. No. 6,288,239 B1 to Hollingsworth and Wang discloses a process for preparing 5-trityloxymethyl-2-oxazolidinones and suggests a scheme for the alkylation of N-lithio-N-substituted carbamates with oxiranes such as glycidyl butyrate as shown in Scheme 1.
Glycidyl equivalents such as epichlorohydrin can be used instead of glycidyl butyrate.
Schaus and Jacobsen (Tetrahedron Letts. 37: 7937-7940 (1996)) teach using optically active N-oxiranylmethylacetamides to prepare chiral 3-(substituted)-5-acetamidomethyl-2-oxazolidinones in one step by the alkylation of N-lithio-N-aryl (or alkyl) carbamates as shown in Scheme 2.

However, the above processes do not allow for the rapid synthesis of a plurality of substituted oxazolidinones at the same time in the same reaction. Thus, producing a plurality of substituted oxazolidinones for drug screening is slow and cumbersome which affects the rate in which new and useful drugs can be discovered. Therefore, there remains a need for a rapid and simple process that can produce a plurality of substituted oxazolidinones at the same time in the same reaction. Being able to produce a plurality of drug candidates in a short period of time would accelerate the rate at which new and useful drugs and other compounds are discovered. The present invention provides a simple and rapid process for synthesizing substituted oxazolidinones.
Strains of Gram positive bacteria resistant to the present repertoire of antibiotics have been increasing in prevalence over the past several decades (Skold, Acta Vet. Scand. Suppl. 93: 23-36 (2000)). Resistant Gram positive that have been commonly encountered include among others those in the staphylococci, streptococci, pneumococci, and enterococci families. Because of the increasing prevalence of these antibiotic resistant bacterial strains, there is a clear need for new antimicrobial agents.
Several species of substituted oxazolidinones have been discovered to be effective antimicrobial agents against particular antibiotic resistant strains of Gram positive bacteria. Linezolid (Clemett and Markham, Drugs 59: 815-827 (2000); Johnson et al., J. Antimicrob. Chemother. 45: 225-230 (2000)) is a substituted oxazolidinone which has been approved for the treatment of microbial infections. The structure of linezolid is shown below.
A number of other substituted oxazolidinones with varying degrees of antibacterial activity against Gram positive and in some cases Gram negative bacteria are also known (Barry, Antimicrob. Agents Chemotherp. 32: 150-152 (1988); Brickner et al., J. Med. Chem. 39: 673-679 (1996); Genin et al., J. Med. Chem. 43: 953-970 (2000); Slee et al., Antimicrob. Agents Chemotherp. 31: 1791-1797 (1987)).
Most, if not all, of the known substituted oxazolidinones which have been found to have antibacterial activity have the structure shown below wherein the R3 substituent is aryl and the relative stereochemistries of the groups on the chiral center (C-5) is as indicated.

A comparison of the structures for all of the known substituted oxazolidinones which have antimicrobial activity, the general consensus has arisen that there are at least three elements of these substituted oxazolidinones which are critical for biological activity. The first element is that when the oxazolidinone ring is oriented as shown below such that all the ring atoms are in one plane, the carbonyl oxygen points up, the ring nitrogen is to the left, and the 5-substituent is to the right, then of the two possible orientations for the 5-substituent (distal or proximal), the proximal substituent is required for biological activity.
The second element is that the 3-substituent is an aryl. The third element is that the 5-substituent is an alkylamino methyl or an acetamidomethyl group. No substituted oxazolidinone which has antibacterial activity has been found which does not have all three of the above elements.
Because microorganisms will eventually develop resistance to antibiotics, there is a continual need for new antibiotics. The present invention provides families of novel substituted oxazolidinones which have antimicrobial activity but which have structures which do not conform to the consensus structure thought to be necessary for antimicrobial activity.